Method of treating epithelial disorders

ABSTRACT

A method for treating skin disorders in warm-blooded animals, said method comprising administering to said warm-blooded animals an effective amount of an appropriately substituted benzimidazole or benzotriazole which suppresses the metabolism of retinoids. Compositions comprising said compounds and an effective amount of a retinoid.

This application is a divisional of application Ser. No. 07/927,571,filed Aug. 10, 1992, now U.S. Pat. No. 5,342,957, which in turn was adivisional of application Ser. No. 07,434,962, filed Nov. 13, 1989, nowU.S. Pat. No. 5,157,046, which in turn was a continuation-in-part ofapplication Ser. No. 07/277,152, filed Nov. 29, 1988, now abandoned.

BACKGROUND OF THE INVENTION

Retinoids, in particular retinoic acid and its derivatives, aresubstances which are known to have a broad spectrum of biologicalactivity. More specifically, these substances affect thedifferentiation, maintenance and proliferation of various cell types.The ability of retinoids, such as, all-trans-retinoic acid,13-cis-retinoic acid, and their derivatives to modulate differentiationin several cell types, whether they are of epithelial or mesenchymalorigin, is extensively studied and reviewed in J. Clin. Chem. Clin.Biochem., 26, 479-488 (1983); Pharmacological Reviews, 36, 935-1005(1984) and Arch. Dermatol., 117, 160-180 (1981).

It is known that certain retinoids, particularly the retinoic acids, areused topically for treatment of acne as set forth in U.S. Pat. No.3,729,568. Other known uses of retinoic acid were reviewed in theJournal of American Academy of Dermatology, 4, 505-516 (1981) and theJournal of Medical Chemistry, 25, 1269-1277 (1982) and include, inaddition to acne treatment, treatment of senile comedones, nevuscomedonicus, linear verrucous nevus, plantar, pseudofolliculitis,keratoacanthoma, solar keratosis of extremities, callosites, keratosispalmaris et plantaris, Darier's disease, ichthyosis, psoriasis,acanthosis nigricans, lichen planus, molluscum contagiosum, reactiveperforating collagenosis, melasma, corneal epithelial abrasion,Fox-Fordyce disease, cutaneous metastatic melanoma and keloids orhypertrophic scars.

Retinoids such as, all-trans-retinoic acid, 13-cis-retinoic acid andtheir derivatives, have also been used in the treatment of carcinomas.

There are however a number of drawbacks associated with the therapeuticapplications of retinoids. The topical applications of retinoids on theone hand often cause significant irritation and peeling due to therelatively high concentrations of retinoid which have to be applied.Systemic applicaticns on the other hand are limited by the toxicity andrapid degradation of the administered retinoids.

The compounds of the invention overcome the problems associated with artknown retinoid therapy by suppressing the metabolism of endogenous orexogenously administered retinoic acid.

DESCRIPTION OF THE INVENTION

The present invention provides a method of treating mammals sufferingfrom disorders which are characterized by an increased proliferationand/or abnormal differentiation of epithelial cells, by the systemic ortopical administration to said mammals of an effective amount of anappropriately substituted benzimidazole or benzotriazole whichsuppresses the plasma elimination of endogenous or exogenouslyadministered retinoic acid. A number of appropriately substitutedbenzimidazoles or benzotriazoles are disclosed in our applications U.S.Pat. No 4,859,684 and U.S. Ser. No. 223,486 which corresponds to EP-A293,978. Particular compounds for use in the present invention arecompounds of formula ##STR1## a pharmaceutically acceptable acidaddition salt thereof or a stereochemically isomeric form thereof,wherein

R, R¹, R², --A¹ ═A² --A³ ═A⁴ -- and A in formula (I) have the followingmeaning --A¹ ═A² --A³ ═A⁴ -- is a bivalent radical having the formula

    --CH═N--CH═CH--                                    (x);

    --CH═N--CH═N--                                     (y); or

    --CH═N--N═CH--                                     (z);

R is hydrogen or C₁₋₆ alkyl;

R¹ is hydrogen; C₁₋₁₀ alkyl; C₃₋₇ cycloalkyl; Ar¹ or Ar¹ --C₁₋₆ alkyl;

R² is hydrogen; C₃₋₇ cycloalkyl; Ar¹ ; C₁₋₁₀ alkyl; C₁₋₆ alkylsubstituted with Ar¹ or C₃₋₇ cycloalkyl; hydroxy; C₁₋₁₀ alkyloxy; C₁₋₆alkyloxy substituted with Ar¹ or C₃₋₇ cycloalkyl; C₃₋₆ alkenyloxyoptionally substituted with Ar² ; C₃₋₆ alkynyloxy optionally substitutedwith Ar² ; or Ar¹ -oxy;

A is a bivalent radical having the formula ##STR2## wherein the carbonatom in the bivalent radical (a) and (b) is connected to --NR² ;

said R³ being hydrogen; halo; C₁₋₄ alkyl substituted with up to 4 haloatoms; C₃₋₇ cycloalkyl; Ar¹ ; quinolinyl; indolinyl; C₁₋₁₀ alkyl; C₁₋₆alkyl substituted with Ar¹, C₃₋₇ cycloalkyl, quinolinyl, indolinyl orhydroxy; C₁₋₁₀ alkyloxy; C₁₋₆ alkyloxy substituted with Ar¹ or C₃₋₇cycloalkyl; C₂₋₆ alkenyl optionally substituted with Ar¹ ; Ar² -oxy;C₁₋₆ alkyloxycarbonyl; carboxyl; C₁₋₆ alkylcarbonyl; Ar¹ -carbonyl orAr¹ --(CHOH)--;

said X being O or S;

said R⁴ being hydrogen, C₁₋₆ alkyl or Ar² --C₁₋₆ alkyl;

wherein Ar¹ is phenyl, substituted phenyl, pyridinyl, aminopyridinyl,imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl; andAr² is phenyl or substituted phenyl; said substituted phenyl in Ar¹ andAr² being phenyl substituted with 1, 2 or 3 substituents eachindependently selected from halo, hydroxy, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkyloxy, cyano, amino, mono- and di(C₁₋₆ alkyl)amino, nitro,carboxyl, formyl and C₁₋₆ alkyloxycarbonyl; and wherein

R, R⁵, R⁶, R⁷ and --A¹ ═A² --A³ ═A⁴ -- in formula (II) have thefollowing meaning --A¹ ═A² --A³ ═A⁴ -- is a bivalent radical having theformula

    --CH═N--CH═CH--                                    (x);

    --CH═N--CH═N--(y); or

    --CH═N--N═CH--                                     (z);

R is hydrogen or C₁₋₆ alkyl;

R⁵ is hydrogen; C₁₋₁₀ alkyl; C₃₋₇ cycloalkyl; Ar³ ; Ar⁴ --C₁₋₆ alkyl;C₂₋₆ alkenyl or C₂₋₆ alkynyl;

R⁶ is hydrogen; C₁₋₁₀ alkyl optionally substituted with Ar³, C₃₋₇cycloalkyl, hydroxy or C₁₋₆ alkyloxy; Ar³ ; C₂₋₆ alkenyl; C₂₋₆ alkynyl;C₃₋₇ cycloalkyl; bicyclo[2.2.1]heptan-2-yl; 2,3-dihydro-1H-indenyl;1,2,3,4-tetrahydronaphthalenyl; or a radical of formula OR⁷,

R⁷ is hydrogen; C₂₋₆ alkenyl optionally substituted with Ar⁴ ; C₂₋₆alkynyl; pyrimidinyl, di(Ar⁴)methyl; 1-C₁₋₄ alkyl-4-piperidinyl; orC₁₋₁₀ alkyl optionally substituted with halo, hydroxy, C₁₋₆ alkyloxy,amino, mono- and di(C₁₋₆ alkyl)-amino, trifluoromethyl, carboxyl, C₁₋₆alkyloxycarbonyl, Ar³, Ar⁴ --O--, Ar⁴ --S--, C₃₋₇ cycloalkyl,2,3-dihydro-1,4-benzodioxinyl, 1H-benzimidazolyl, C₁₋₄ alkyl substituted1H-benzimidazolyl, (1,1'-biphenyl)-4-yl or with2,3-dihydro-2-oxo-1H-benzimidazolyl;

R⁸ is hydrogen, nitro, amino, mono- and di(C₁₋₆ alkyl)amino, halo, C₁₋₆alkyl, hydroxy or C₁₋₆ alkyloxy;

wherein Ar³ is phenyl, substituted phenyl, naphthalenyl, pyridinyl,aminopyridinyl, imidazolyl, triazolyl, thienyl, halothienyl, furanyl,C₁₋₆ alkylfuranyl, halofuranyl or thiazolyl; Ar⁴ is phenyl, substitutedphenyl or pyridinyl, said substituted phenyl in Ar³ and Ar⁴ being phenylsubstituted with up to 3 substituents each independently selected fromhalo, hydroxy, hydroxymethyl, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆alkyloxy, C₁₋₆ alkyloxycarbonyl, carboxyl, formyl, (hydroxyimino)methyl,cyano, amino, mono- and di(C₁₋₆ alkyl)amino and nitro. Preferably saidsubstituted phenyl is phenyl substituted with one or two substituentseach independently selected from halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy andtrifluoromethyl.

As used in the foregoing definitions the term halo is genetic to fluoro,chloro, bromo and iodo; the term "C₁₋₆ alkyl" is meant to includestraight chained and branched saturated hydrocarbon radicals having from1 to 6 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and thelike; "C₁₋₁₀ alkyl" is meant to include C₁₋₆ alkyl radicals, as definedhereinabove, and the higher homologs thereof having from 7 to 10 carbonatoms; the term "C₃₋₇ cycloalkyl" is genetic to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. "C₂₋₆ alkenyl" defines straightchained and branched hydrocarbon radicals containing one double bondhaving from 2 to 6 carbon atoms such as, for example, ethenyl,2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl and the like; "C₂₋₆ alkynyl" defines straight chainedand branched hydrocarbon radicals containing one triple bond and havingfrom 2 to 6 carbon atoms such as, for example, 2-propynyl, 2-butynyl,3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and the like; and when aC₂₋₆ alkenyl or a C₂₋₆ alkynyl is substituted on a heteroatom, then thecarbon atom of said C₂₋₆ alkenyl or said C₂₋₆ alkynyl connected to saidheteroatom preferably is saturated.

It is to be understood that the ##STR3## both hereinafter refered as the1H-azol-1-ylmethyl moiety, may be substituted on either the 4, 5, 6 or 7position of the benzimidazole or benzotriazole heterocyclic ring,preferably on the 5 or 6 position, with the 5 position being preferred.

It is evident that the compounds of formula (I) may also contain intheir structure a tautomeric system and consequently these compounds canbe present in each of their tautomeric forms.

Particular compounds for use in the method of the present invention arethose compounds of formula (I) wherein the 1H-azol-1-ylmethyl moiety issubstituted on either the 5 or 6 position of the benzimidazole ring;and/or R is hydrogen; and/or R¹ is hydrogen; C₁₋₆ alkyl; C₃₋₇cycloalkyl; phenyl; substituted phenyl; thienyl or furanyl optionallysubstituted with halo; and/or R² is hydrogen; C₃₋₇ cycloalkyl; phenyl;substituted phenyl; pyridinyl; C₁₋₆ alkyl optionally monosubstitutedwith phenyl, C₃₋₇ cycloalkyl, pyridinyl or thienyl; hydroxyl, C₁₋₆alkyloxy optionally monosubstituted with phenyl, pyridinyl, thienyl orC₃₋₆ cycloalkyl; C₃₋₆ alkenyloxy optionally monosubstituted with phenyl;or C₃₋₆ alkynyloxy; and/or R³ is hydrogen; C₁₋₄ alkyl substituted withup to 4 halo atoms; C₃₋₇ cycloalkyl; phenyl; substituted phenyl;imidazolyl; thiazolyl; thienyl; furanyl; quinolinyl; pyridinyloptionally substituted with amino, C₁₋₁₀ alkyl; C₁₋₅ alkyl optionallymonosubstituted with phenyl, pyridinyl, imidazolyl, thienyl, indolyl orhydroxyl; C₁₋₄ alkyloxy optionally monosubstituted with phenyl; C₂₋₆alkenyl optionally monosubstituted with pyridinyl, furanyl, imidazolylor phenyl; carboxyl; C₁₋₄ alkyloxycarbonyl; phenylcarbonyl; or hydroxyand phenylmethyl; and/or R⁴ is hydrogen or phenyl C₁₋₄ alkyl.

Other particular compounds for use in the method of the presentinvention are those compounds of formula (II) wherein the1H-azol-1-ylmethyl moiety is substituted on either the 5 or 6 positionof the benzotriazole ring; and/or R is hydrogen; and/or R⁵ is hydrogen;C₁₋₆ alkyl; phenyl; substituted phenyl; C₃₋₇ cycloalkyl; thienyl orfuranyl optionally substituted with halo; and/or R⁶ is hydrogen; C₁₋₆alkyl; C₃₋₆ alkenyl; C₃₋₆ alkynyl; C₃₋₇ cycloalkyl; phenyl; substitutedphenyl; bicylo[2.2.1]heptan-2-yl; 2,3-dihydro-1H-indenyl;1,2,3,4-tetrahydronaphthalenyl; C₁₋₆ alkyl monosubstituted with phenyl,substituted phenyl, naphthalenyl, thienyl, furanyl, C₁₋₄ alkylfuranyl,C₃₋₇ cycloalkyl, hydroxy, C₁₋₄ alkyloxy; or R⁶ is a radical --OR⁷ withR⁷ being hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, phenylC₃₋₆ alkenyl, C₃₋₆alkynyl, pyrimidinyl, diphenylmethyl, (1-C₁₋₄ alkyl-4-piperidinyl), C₁₋₆alkyl substituted with halo, hydroxy, amino, mono-or di(C₁₋₆alkyl)amino, trifluoromethyl, carboxyl, C₁₋₆ alkyloxycarbonyl, phenyl,substituted phenyl, thienyl, furanyl, C₁₋₄ alkylfuranyl, pyridinyl,phenoxy, phenylthio, 2,3-dihydro-1,4-benzodioxinyl, 1H-benzimidazolyl,C₁₋₄ alkyl substituted 1Hbenzimidazolyl, (1,1'-biphenyl)-4-yl or2,3-dihydro-2-oxo-1H-benzimidazolyl; and/or R⁸ is hydrogen.

More particular compounds for use in the method of the present inventionare those particular compounds of formula (I) wherein R¹ is hydrogen,C₁₋₆ alkyl, phenyl, substituted phenyl, thienyl or furanyl; R² ishydrogen, C₁₋₆ alkyl, or C₁₋₄ alkyl substituted with phenyl; R³ ishydrogen, C₁₋₆ alkyl, phenyl, pyridinyl, C₁₋₆ alkyl, C₁₋₆ alkylmonosubstituted with phenyl or C₂₋₆ alkenyl optionally monosubstitutedwith furanyl or phenyl; and R⁴ is hydrogen.

Other more particular compounds of the present invention are thoseparticular compounds of formula (II) wherein R⁵ is hydrogen, C₁₋₆ alkyl,phenyl, substituted phenyl, thienyl or furanyl; R⁶ is hydrogen, C₁₋₆alkyl, C₁₋₆ alkyl substituted with phenyl, or a radical of formula --OR⁷with R⁷ being hydrogen or C₁₋₆ alkyl.

Preferred compounds for use in the method of the present invention arethose particular compounds of formula (I) wherein R¹ is C₁₋₄ alkyl,phenyl, phenyl substituted with one or two halo, C₁₋₄ alkyl or C₁₋₄alkyloxy substituents, or thienyl; R² is hydrogen or C₁₋₄ alkyl; and R³is hydrogen or C₁₋₄ alkyl.

Other preferred compounds for use in the method of the present inventionare those particular compounds of fomula (II) wherein R⁵ is C₁₋₄ alkyl,phenyl or phenyl substituted with one or two halo, C₁₋₄ alkyl or C₁₋₄alkyloxy substituents; and R⁶ is hydrogen or C₁₋₄ alkyl.

More preferred compounds for use in the method of the present inventionare those preferred compounds of formula (I) wherein R¹ is phenyl orhalophenyl, and R² and R³ are both independently hydrogen or C₁₋₄ alkyl.

Other more preferred compound for use in the method of the presentinvention are those preferred compounds of formula (II) wherein R⁵ isphenyl or halophenyl and R⁶ is hydrogen or C₁₋₄ alkyl.

Most preferred compounds for use in the method of the present inventionare 5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzimidazole,(±)-5-[(1H-imidazol-1-yl)phenylmethyl]-2-methyl-1H-benzimidazole,5-[(1H-imidazol-1-yl)phenylmethyl]-1-methyl-1H-benzimidazole,5-[1-(1H-imidazole-1-yl)-2-methylpropyl]-2-methyl-1H-benzimidazole,5-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]-1H-benzimidazole or(±)-5-[(1H-imidazol-1-yl)phenylmethyl]-2-methyl-1H-benzimidazole, thepharmaceutically acceptable acid addition salts and possiblestereoisomers thereof.

The compounds of formula (I) and (II) can be prepared by N-alkylating anazole of formula (III) or an alkali metal salt thereof with abenzimidazole of formula (IV) or a benzomazole of formula (V). ##STR4##In formula (IV) and (V) W represents an appropriate reactive leavinggroup such as, for example, halo, e.g. fluoro, chloro, bromo, iodo or asulfonyloxy group, e.g. 4-methylbenzenesulfonyloxy, benzenesulfonyloxy,2-naphthalenesulfonyloxy, methanesulfonyloxy,trifluoromethanesulfonyloxy and the like reactive leaving groups.

The above described N-alkylations are conveniently carried out by stimngthe reactants in the presence of a suitable solvent such as, forexample, an aromatic hydrocarbon, e.g., benzene, methylbenzene,dimethylbenzene, and the like; an ester, e.g. ethyl acetate,γ-butyrolacetone and the like; a ketone, e.g. 2-propanone,4-methyl-2-penta-none and the like; an ether, e.g., 1,4-dioxane,1,1'-oxybisethane, tetrahydrofuran and the like; a polar aproticsolvent, e.g., N,N-dimethylformamide, N,N-dimethyl-acetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, acetonitrile, hexamethyl-phosphortriamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethyl-2-imidazolidinone, benzonitrile and the like; and mixturesof such solvents. Somewhat elevated temperatures may be appropriate toenhance the rate of the reaction and in some cases the reaction may evenbe carried out at the reflux temperature of the reaction mixture. Theaddition of an appropriate base such as, for example, an alkali or anearth alkaline metal carbonate, hydrogen carbonate, hydroxide, amide orhydride, e.g., sodium hydroxide, potassium hydroxide, potassiumcarbonate, sodium hydride and the like or an organic base, such as, forexample, N,N-dimethyl-4-pyridinamine, pyridine, N,N-diethylethanamine orN-(1-methylethyl)-2-propanamine may be employed to pick up the acidwhich is liberated during the course of the reaction. In some instancesit may be advantageous to use an excess of the azole (Ill) or to convertthe azole first into a suitable salt form thereof such as, for example,an alkali or earth alkaline metal salt, by reacting (III) with anappropriate base as defined hereinabove and subsequently using said saltform in the reaction with the alkylating reagents of formulae (IV) or(V). Additionally, it may be advantageous to conduct said N-alkylationreaction under an inert atmosphere such as, for example, oxygen-freeargon or nitrogen gas. Said alkylation may also be carried out byapplying art-known conditions of phase transfer catalysis reactions.

Compounds of formula (I) and (II) wherein --X¹ ═X² -- is a bivalentradical of formula (x), said compounds being represented by formula(I-x) and (II-x), may also be prepared by reacting a benzimidazole (IV)or benzotriazole (V) with a 1-protected imidazole of formula (III-x)following the N-alkylation procedures described hereinabove for thepreparation of compounds of formula (I) or (II) starting from (III) and(IV) and from (III) and (V). ##STR5##

In (III-x) P¹ represents a protective group such as, for example, C₁₋₆alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, arylcarbonyl or a tri(C₁₋₆alkyl)silyl group. In some instances the reaction of (III-x) with (IV)or (V) first yields a 1-protected imidazolium salt of formula (VI-a) or(VI-b) which may in situ, or if desired, after isolating and furtherpurifying it, be deprotected by stirring it in an aqueous basic solutionor acidic solution. ##STR6##

In (VI-a) and (VI-b) W⁻ is an anion arising from an acid such as, forexample, hydrochloric acid, hydrobromic acid, methanesulfonic acid,4-methylbenzenesulfonic acid and the like acids.

Compounds of formula (I) and (II) wherein --X¹ ═X² -- is a bivalentradical of formula (y), said compounds being represented by formula(I-y) and (II-y), can also be prepared by endo-N-alkylation of atriazolamine of formula (III-y) with a benzimidazole (IV) and abenzotriazole (V) and subsequent deamination of the thus preparedtriazolium salt, wherein W- is an anion as defined hereinabove. ##STR7##

The endo-N-alkylation reaction of (III-y) with (IV) or (V) is carriedout according to similar procedures as described hereinabove for thepreparation of a compound of formula (I) starting from (III) and (II).Said deamination reaction is conveniently conducted by reaction with anacidic nitrite solution in the presence of an appropriate reductant, orby reaction with an alkylnitrite such as, for example,1,1-dimethylethylnitrite or isoamylnitrite and the like. Preferably,said deamination reaction is conducted with an aqueous solution ofnitrous acid or of a nitrite salt in a suitable acid in the presence ofa reducing agent such as, for example, hypophosphorous acid, formicacid, at a lower temperature.

The compounds of formulae (I) and (II) may also be prepared by reactingan intermediate of formula (VII) or (VIII) with a reagent of formula(IX) such as, for example, a 1,1'-carbonylbis[1H-imidazole]. ##STR8##Said reactions may conveniently be conducted in a suitable solvent suchas, for example, an ether, e.g., 1,4-dioxane, tetrahydrofuran; ahalogenated hydrocarbon, e.g., di- or trichloromethane; a hydrocarbon,e.g., benzene, methylbenzene; N,N-dimethylformamide,N,N-dimethylacetamide, or mixtures of such solvents. In order to enhancethe reaction rate, it may be advantageous to heat the reaction mixture.

The compounds of formula (I) may also be prepared by reacting a ketoneor aldehyde of formula (X) or (XI) with an azole (III) in the presenceof formic acid or formamides as reducing agents. ##STR9##

The compounds of formula (I) and (II) can alternatively be preparedaccording to cyclization procedures outlined in the art for thepreparation of benzimidazoles from benzenediamines or orthonitrobenzeneamines, e.g. U.S. Pat. No. 4,859,684, or for the preparationof benzotriazoles starting from appropriate benzenediamines orhalonitrobenzene derivatives, e.g. U.S. Ser. No. 223,486, whichcorresponds to EP-A-293,978.

For example, benzimidazoles of formula (I) can be prepared by cyclizingan appropriately substituted 1,2-benzenediamine with a carboxylic acidor a functional derivative thereof such as, for example the halide,anhydride, amide and ester form thereof in a suitable acidic medium. Theabove and similar cyclization procedures for making the compounds offormula (I) are outlined in U.S. Pat. No. 4,859,684 which isincorporated herein by reference.

The benzotriazoles of formula (II) wherein R⁶ is other than OR⁷, saidcompounds being represented by formula (II-a) and said radical byR^(6-a), can generally be prepared from an appropriate aromatic diamineof formula (XII) by reaction with a suitable diazotizing reagent.##STR10##

Suitable diazotizing reagents are alkylnitrites, e.g.1,1-dimethylethylnitrite, isoamylnitrite and the like; nitroniumtetrafluoroborate, nitrous acid in aqueous solution, or moreparticularly aqueous solutions of nitrite salts such as, for example,sodium nitrite, potassium nitrite, silver nitrite and the like, in thepresence of a mineral and/or organic acid such as, for example,hydrohalic acids, e.g. hydrochloric, hydrobromic and the like acids;perchloric acid, perbromic acid, periodic acid, phosphoric acid,sulfuric acid, nitric acid and the like; carboxylic acids, e.g. formic,acetic, trifluoroacetic, propanoic, benzoic, methanesulfonic and thelike acids.

Said reaction can conveniently be conducted by stirring the aromaticdiamine of formula (XII) in the presence of a suitable diazotizingreagent as defined hereinabove, at a low temperature, in an aqueoussolution, optionally in admixture with organic cosolvents such as, forexample, alkanols, e.g. methanol, ethanol and the like.

The compounds of formula (II) wherein R⁷ is other than hydrogen, saidcompounds being represented by formula (II-b) and said radical byR^(7-a), can generally be prepared by O-alkylating a compound of formula(II) wherein R⁷ is hydrogen, said compounds being represented by formula(II-c), with an appropriate alkylating reagent of formula R^(7a) --W(XIII). ##STR11## In formula (XIII) and hereinafter W represents anappropriate reactive leaving group such as, for example, halo, e.g.chloro, bromo, iodo, or a sulfonyloxy group, e.g.4-methylbenzenesulfonyloxy, benzenesulfonyloxy,2-naphthalenesulfonyloxy, methanesulfonyloxy,trifluoromethanesulfonyloxy and the like reactive leaving groups.

Said O-alkylation reaction can conveniently be carried out by mixing thereactants, optionally in a reaction-inert solvent such as, for example,water, an aromatic solvent, e.g. benzene, methylbenzene,dimethylbenzene, chlorobenzene, methoxybenzene and the like; a C₁₋₆alkanol, e.g. methanol, ethanol, 1-butanol and the like; a ketone, e.g.2-propanone, 4-methyl-2-pentanone and the like; an ester, e.g. ethylacetate, γ-butyrolactone and the like; an ether, e.g. 1,1'-oxybisethane,tetrahydrofuran, 1,4-dioxane and the like; a dipolar aprotic solvent,e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethyl-2-imidazolidinone, 1,1,3,3-tetramethylurea,1-methyl-2-pyrrolidinone, nitrobenzene, acetonitrile and the like; or amixture of such solvents. The addition of an appropriate base such as,for example, an alkali metal or an earth alkaline metal carbonate,hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride oramide, e.g. sodium carbonate, sodium hydrogen carbonate, potassiumcarbonate, sodium hydroxide, calcium oxide, sodium acetate, sodiummethoxide, sodium hydride, sodium amide and the like, or an organic basesuch as, for example, an amine, e.g. N,N-diethylethanamine,N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine,1,4-diazabicyclo[2.2.2]octane, pyridine and the like, may optionally beused to pick up the acid which is formed during the course of thereaction. Further, it may be advantageous to convert the compound (II-c)fast into a suitable salt form thereof such as, for example, an alkalior earth alkaline metal salt, by reacting (II-c) with an appropriatebase as defined hereinabove and subsequently using said salt form in thereaction with the alkylating reagent of formula (XIII). In someinstances the addition of an iodide salt, preferably an alkali metaliodide, or a crown ether, e.g. 1,4,7,10,13,16-hexaoxacyclooctadecane andthe like, may be appropriate. Stirring and somewhat elevatedtemperatures may enhance the rate of the reaction; more in particularthe reaction may be conducted at the reflux temperature of the reactionmixture. Additionally, it may be advantageous to conduct saidO-alkylation under an inert atmosphere such as, for example, oxygen-freeargon or nitrogen gas.

Alternatively, said O-alkylation may be carried out by applyingart-known conditions of phase transfer catalysis reactions. Saidconditions comprise stirring the reactants, with an appropriate base andoptionally under an inert atmosphere as defined hereinabove, in thepresence of a suitable phase transfer catalyst such as, for example, atrialkylphenylmethylammonium, tetraalkylammonium, tetraalkylphosphonium,tetraarylphosphonium halide, hydroxide, hydrogen sulfate and the likecatalysts. Somewhat elevated temperatures may be appropriate to enhancethe rate of the reaction.

The compounds of formula (II-c) in turn can be prepared by cyclizing anappropriately substituted nitrobenzene derivative of formula (XIV)wherein W¹ represents a reactive leaving group, with hydrazine, ahydrate thereof or an acid addition salt thereof. ##STR12##

The reactive leaving group W¹ represents, groups such as, for example,halo, e.g. chloro, bromo or preferably fluoro, nitro, sulfonyloxygroups, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxy and thelike, aryloxy, C₁₋₆ alkyloxy or C₁₋₆ alkylthio and the like groups. Saidcyclization may be carded out by stirring the reactants in areaction-inert solvent such as, for example, an alkanol, e.g. methanol,ethanol, 2-propanol, 1-butanol and the like, an aromatic hydrocarbon,e.g. benzene, methylbenzene, dimethylbenzene and the like, or a mixtureof such solvents. Somewhat elevated temperatures may be appropriate toenhance the rate of the reaction and preferably the reaction is camm outat the reflux temperature of the reaction mixture.

The compounds of formula (II-a) wherein R^(7-a) is hydrogen, saidcompounds being represented by formula (II-a-1) may also be preparedfrom the compounds of formula (II-c) following an-known reductionprocedures. ##STR13##

Said reduction may be conducted, for example, by catalytic hydrogenationin the presence of hydrogen and an appropriate hydrogenation catalystsuch as, for example, platinum, palladium, platinum(IV) oxide,Raney-nickel and the like, in the presence of a reaction inert organicsolvent such as, for example, an alkanol, e.g. methanol, ethanol,2-propanol, butanol and the like.

Said reduction may alternatively be conducted by reducing the startingmaterial with a reducing agent such as, for example,titanium(III)chloride or tin(II)chloride in hydrochloric acid,optionally in the presence of a reaction-inert solvent. Preferably saidreduction is camed out by converting the hydroxy group into a, readilyleaving group, such as, for example, an ether --O--CH₂ --Z wherein Z isan electronwithdrawing group such as cyano, C₁₋₆ alkyloxycarbonyl,aminocarbonyl, mono- or di(C₁₋₆ alkyl)aminocarbonyl and the like, byreaction with an O-alkylating reagent of formula W--CH₂ --Z, andstirring the thus obtained ether intermediates in the presence of a basesuch as, for example, an alkali or earth alkaline metal carbonate,hydrogen carbonate, hydroxide, alkoxide or amide, in an appropriatesolvent such as, for example, a dipolar aprotic solvent, e.g. dimethylsulfoxide, N,N-dimethylformamide and the like solvents, thus eliminatingOHC--Z and yielding the desired benzotriazole of formula (II-a-1). SaidO-alkylation and elimination can easily be conducted in a one-potprocedure.

The compounds of formula (II) wherein R⁶ is other than hydrogen and OR⁷,said compounds being represented by formula (II-a-2) and said radical byR^(6-b), may be prepared by N-alkylating a compound of formula (II-a-1)with a reagent of formula RR^(6-b) --W, wherein W is a leaving group asdefined hereinabove. ##STR14##

Said N-alkylation reaction of (I-a-1) may conveniently be conductedfollowing the procedures described hereinabove for the preparation ofthe compounds of formula (II-b) from the compounds of formula (II-c).

Alternatively, some compounds of formula (I) and (II) may also beprepared according to procedures analogous to those described in theliterature for the preparation of azoles by cyclizing an appropriatestarting material.

The compounds of formula (I-x) and (II-x) may also be prepared, forexample, by cyclizing an intermediate of formula (XV) or (XVI) anddesulfurating the thus obtained intermediate of formula (XVII) or(XVIII). ##STR15##

In formulae (XV) and (XVI) and (XVII) and (XVIII) R⁹ representinghydrogen or C₁₋₆ alkyl and R¹⁴ represents C₁₋₆ alkyl or both R¹⁰ takentogether form a C₂₋₃ alkanediyl radical.

Said cyclization reaction may conveniently be conducted by stirring andheating an intermediate (XV) or (XVI) in an aqueous acidic solvent, e.g.in aqueous hydrochloric or sulfuric acid. The thus obtained intermediate(XVII) or (XVIII) may be desulfurated following art-known procedures,e.g., by treatment with Raney nickel in the presence of an alkanol, e.g.methanol, ethanol and the like, or by treatment with nitric acid,optionally in the presence of sodium nitrite.

The compounds of formula (I-y) and (II-y) may be prepared from ahydrazine derivative of formula (XIX) or (XX) by reaction withs-triazine following the procedures described in J. Org. Chem., 1956,1037. ##STR16##

The intermediate hydrazine (XIX) or (XX) and the correspondingintermediate amines may also be convened into azoles, wherein --A¹ ═A²--A³ ═A⁴ -- is a bivalent radical of formula (x), (y) or (z) followingprocedures described in U.S. Pat. No. 4,267,179, incorporated herein byreference.

The intermediates and the starting materials in the foregoing are knownand may be prepared according to art-known methodologies of preparingsaid or similar compounds. Intermediates and starting compounds in thepreparation are specifically described in U.S. Pat. No. 4,859,684 whichis incorporated herein by reference. Intermediates of formula (II) aredescribed in U.S. Ser. No. 223,486 which corresponds to EP-A-293,978. Anumber of such preparation methods will be described hereinafter in moredetail.

The intermediates of formula (XII) can generally be prepared from thecorresponding nitro derivatives of formula (XXI) by reaction with anappropriate reducing agent. ##STR17##

Suitable reducing agents for use in the above nitro-to-amine reductionare, for example, hydrogen in the presence of an appropriatehydrogenation catalyst such as, for example, palladium-on-charcoal,platinum-on-charcoal, Raney-nickel and the like catalysts. Saidreduction can conveniently be conducted in a reaction inert solvent suchas, for example, an alkanol, e.g. methanol, ethanol, 2-propanol and thelike, optionally at an elevated pressure and/or temperature.Alternatively said reduction can also be conducted by reacting the nitroderivative (XXI) with a reducing agent such as sodium dithionate inwater optionally in admixture with an alkanol, e.g. methanol, ethanoland the like.

The nitro derivative (XXI) in turn can be prepared from an intermediate(XXIII) by reaction with a suitable amine of formula (XXII). ##STR18##Said reaction can conveniently be conducted by stirring and, if desired,heating the reactants in a reaction-inert solvent such as, for example,an alkanol, e.g. methanol, ethanol, propanol, butanol, 1,2-ethanedioland the like, an ether, e.g. 1,1'-oxybisethane, tetrahydrofuran,1,4-dioxane and the like a dipolar aprotic solvent, e.g.N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like, ahalogenated solvent, e.g. trichloromethane, tetrachloromethane and thelike; or a mixture of such solvents. The addition of a suitable base topick up the acid which is liberated during the reaction may beappropriate; particularly convenient however is the use of an excess ofthe amine of formula (XXII).

The intermediates of formula (XXIII) can conveniently be prepared bynitration of a benzene derivative of formula (XXIV) following art-knownnitration procedures. ##STR19## Said nitration reaction is convenientlyconducted by treating the intermediate (XXIV) with nitric acid or thenitrate salt of (XXIV), in the presence concentrated sulfuric acid atlow or ambient temperature. In some instances it may be appropriate toheat the reactants. Said nitration can be conducted without anadditional solvent or may also be performed in a suitable solvent suchas, for example, a halogenated hydrocarbon, e.g. trichloromethane,tetrachloromethane and the like, a carboxylic acid or a derivativethereof, e.g. acetic acid, acetic anhydride and the like solvents.

The intermediate hydrazines (XIX) or (XX) and amines may conveniently beprepared from a ketone of formula (X) or (XI) or by reaction with eitheran acid addition salt thereof, or with hydroxylamine or hydrazine or anacid addition salt or a solvate thereof, and reducing the thus obtainedoxime or hydrazone, for example, by catalytic hydrogenation in thepresence of hydrogen and an appropriate hydrogenation catalyst, e.g.Raney nickel and the like.

The intermediates of formula (XV) and (XVI) can be prepared from thecorresponding amines of formula (XXV) and (XXVI) by reaction with areagent of formula (XXVII) and optionally S-alkylating the thus obtainedthiourea with a C₁₋₆ alkylhalide. ##STR20##

From formulae (I) and (II) it is evident that the compounds of thisinvention may have several asymmetric carbon atoms in their structure.Each of these chiral centers may be present in a R- and aS-configuration, this R- and S-notation being in correspondence with therules described by R. S. Cahn, C. Ingold and V. Prelog in Angew. Chem.,Int. Ed. Engl., 5, 385,511 (1966).

Pure stereochemically isomeric forms of the compounds of formulae (I)and (II) may be obtained by the application of art-known procedures.Diastereoisomers may be separated by physical separation methods such asselective cyrstallization and chromatographic techniques, e.g., countercurrent distribution, and enantiomers may be separated from each otherby the selective crystallization of their diastereomeric salts withoptically active acids.

Pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically.

Stereochemically isomeric forms of the compounds of formulae (I) and(II) are naturally intended to be embraced within the scope of theinvention.

An additional feature of the invention comprises the fact that thosecompounds of formula (I) wherein --A¹ ═A² --A³ ═A⁴ -- is a bivalentradical of formula (y) or (z) or wherein --A¹ ═A² --A³ ═A⁴ -- is abivalent radical of formula (x) and R is C₁₋₆ alkyl, thepharmaceutically acceptable acid addition salts thereof and thestereochemically isomeric forms thereof are novel compounds.

Particular novel compounds are those novel compounds wherein --A¹ ═A²--A³ ═A⁴ -- is a bivalent radical of formula (y) or (z).

Preferred novel compounds within the invention are those particularnovel compounds wherein --A¹ ═A² --A³ ═A⁴ -- is a bivalent radical offormula (y); and/or R¹ is phenyl or halophenyl; and/or R² is hydrogen orC₁₋₄ alkyl; and/or R³ is hydrogen or C₁₋₄ alkyl.

Some of the compounds of formula (I) and (II) which can be used asactive ingredient in the compositions and methods of treatment accordingto the present invention are listed in the following tables with thepurpose of illustrating the invention and not to limit it thereto.

                                      TABLE 1                                     __________________________________________________________________________     ##STR21##                                                                    Comp                                                                          No. p*                                                                              A.sup.1 A.sup.2 A.sup.3 A.sup.4                                                            R.sup.1    R.sup.2  R.sup.3      mp.                       __________________________________________________________________________                                                        (°C.)/salt          1  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H        H            186.2                      2  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H        CH.sub.3     118.4                      3  5 CHCHNCH      2-thienyl- H        H            101.0                      4  5 CHCHNCH      2-thienyl- H        CH.sub.3     108.9                      5  5 CHCHNCH      4-FC.sub.6 H.sub.4                                                                       H        CH.sub. 3    110.6                      6  5 CHCHNCH      2,4-(Cl).sub.2 C.sub.6 H.sub.3                                                           H        CH.sub.3     138.4                      7  5 CHCHNCH      3-ClC.sub.6 H.sub.4                                                                      H        CH.sub.3     113.3                      8  5 CHCHNCH      3-CH.sub.3 C.sub.6 H.sub.4                                                               H        H            104.8                      9  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H        2-pyridyl-   123.3                     10  5 CHCHNCH      c.C.sub.3 H.sub.5                                                                        H        H             73.5                     11  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H        3-pyridiyl-  133.1                     12  6 NCHNCH       H          OH       3-pyridiyl-  219.3                     13  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H        C.sub.6 H.sub.5                                                                            134.5                     14  6 NCHNCH       H          OCH.sub.3                                                                              3-pyridiyl-  141.5                     15  5 NCHNCH       H          H        CH.sub.3     241.0/2HCl                16  5 NCHNCH       H          H        H            184.4                     17  5 NCHNCH       H          H        C.sub.6 H.sub.5                                                                            239.7                     18  5 NCHNCH       H          H        3-pyridiyl-  222.5                     19  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H        C.sub.6 H.sub.5 CH.sub.2                                                                   189.9                     20  5 CHCHNCH      C.sub.4 H.sub.9                                                                          H        CH.sub.3     --                        21  5 CHCHNCH      C.sub.6 H.sub.5                                                                          CH.sub.3 H            138.7                     22  5 CHCHNCH      i-C.sub.3 H.sub.7                                                                        H        CH.sub.3     214.8/2HCl/H.sub.2 O      23  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H                                                                                       ##STR22##   134.7 (E)                 24  5 CHCHNCH      C.sub.3 H.sub.7                                                                          H        CH.sub.3     174.2/1.5(COOH).sub.2                                                         1                         25  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H                                                                                       ##STR23##   140.6 (E)                 26  5 CHCHNCH      2-furanyl- H        H            150.9                     27  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H        CH.sub.3      77.2/H.sub.2 O/**        28  5 CHCHNCH      3-ClC.sub.6 H.sub.4                                                                      H        H            200.2/HCl                 29  5 CHCHNCH      3-ClC.sub.6 H.sub.4                                                                      CH.sub.3 H            131.2/1/2H.sub.2 O        30  5 CHCHNCH      3-ClC.sub.6 H.sub.4                                                                      C.sub.6 H.sub.5 CH.sub.2                                                               H             59.6/1/2EtOH             31  5 NCHNCH       3-ClC.sub.6 H.sub.4                                                                      H        CH.sub.3     205.4/2(COOH).sub.2       32  5 NCHNCH       3-ClC.sub.6 H.sub.4                                                                      H        H            210.0                     33  5 CHCHNCH      C.sub.6 H.sub.5                                                                          H        CH.sub.3     128.5/H.sub.2             __________________________________________________________________________                                                        O                          *:p indicates the position of the 1.sub.-- Hazol-1-ylmethylmoiety on the      benzimidazole ring                                                            ** = [α].sub.D = -29.57° (c = 0.5% in methanol)             

                                      TABLE 2                                     __________________________________________________________________________     ##STR24##                                                                    Comp.                                                                         No. A.sup.1 A.sup.2 A.sup.3 A.sup.4                                                           p*                                                                              R.sup.5 R.sup.6                                                                           mp. (°C.)/salt                           __________________________________________________________________________    34  CHCHNCH     5 C.sub.6 H.sub.5                                                                       CH.sub.3                                                                          111.9/HNO.sub.3                                 35  CHCHNCH     5 C.sub.6 H.sub.5                                                                       H   178.8                                           36  CHCHNCH     6 C.sub.6 H.sub.5                                                                       CH.sub.3                                                                          102.7                                           37  NCHNCH      5 C.sub.6 H.sub.5                                                                       H   182.7                                           38  CHCHNCH     6 4-ClC.sub.6 H.sub.4                                                                   CH.sub.3                                                                          151.5/HCl/H.sub.2 O                             39  NCHNCH      6 4-ClC.sub.6 H.sub.4                                                                   CH.sub.3                                                                          178.9                                           __________________________________________________________________________     *p indicates the position of the 1.sub.-- H-azol-1-ylmethyl moiety on the     benzotriazole ring.                                                      

The use of the compounds of formula (I) and (II), their pharmaceuticallyacceptable acid addition salts and their possible stereochemicallyisomeric forms in the method of the present invention is based on theiruseful property to delay the metabolism of retinoids, such as,all-trans-retinoic acid, 13-cis-retinoic acid and their derivatives. Thelatter results in more sustained/higher tissue concentrations ofretinoids and improved control of differentiation and growth of variouscell types. Said property to delay the metabolism of retinoids caneasily be evidenced in various in vivo experiments. A particular testprocedure is described hereinafter as the "Metabolism of endogenous orexogenously administered all-trans-retinoic acid"-test. As such, thecompounds of formula (I) and (II) can be used to control the rate ofgrowth and differentiation of normal, preneoplastic and neoplasticepithelial cells. The ability of retinoids, such as, 13-cis-retinoicacid, all-trans-retinoic acid and their derivatives to modulatedifferentiation and proliferation in several cell types is extensivelystudied and reviewed in J. Clin. Chem. Clin, Biochem., 26, 479-488(1983); Pharmacological Reviews 36, 935-1005,(1984),Arch. Dermatol. 117,160-180; (1981) and Journal of Medicinal Chemistry 25, 1269-1277,(1982).

The compounds of formulae (I) and (II), their pharmaceuticallyacceptable acid addition salts and their possible stereochemicallyisomeric forms are therefore useful in a method of treating disorderswhich are characterized by an increased proliferation and/or abnormaldifferentiation of epithelial cells. In particular the compounds of theinvention can be used for treatment of carcinoma, which is essentially aderailment of cellular differentiation occurring in epithelial tissues.The compounds of the invention do not only exhibit an anticarcinogeniceffect on estrogen or androgen dependent carcinoma cells but also showan unexpected effect on cells of which the growth and differentiation isnot substantially mediated by or insensitive to the actions of androgensor estrogens, in particular on cells of which the growth anddifferentiation is sensitive to the actions of retinoids. Other usesinclude the ability to cure and/or reduce a variety of disorders ofkeratinization such as, for example, acne, psoriasis, lameliarichthyosis, plantar warts, callosites, acanthosis nigricans, lechenplanus, molluscum, melasma, corneal epithelial abrasion, geograpictongue, Fox-Fordyce disease, cutaneous metasiatic melanoma and heloids,epidermolytic hyperkeratosis, Darier's disease, pityriasis rubrapilaris, congenital icthyosiform erythroderma, hyperkeratosis palmariset plantaris, and similar disordes.

The anti-tumor activity, especially in retinoic acid sensitive tumors,may be demonstrated in several retinoic acid-sensitive cell lines andsolid tumors such as, for example, in Ta3-Ha induced mamma tumors infemale mice.

Those of skill in treating disorders which are characterized by anexcessive proliferation and/or abnormal differentiation of tissues coulddetermine the effective amount from the test results presentedhereinafter. In general it is contemplated than an effective amountwould be from 0.001 mg/kg to 50 mg/kg body weight and more preferablyfrom 0.01 mg/kg to 10 mg/kg body weight.

The compounds of formulae (I) and (II) used the method of the inventionare most preferably applied in the form of appropriate compositions. Asappropriate compositions there may be cited all compositions usuallyemployed for systemically or topically administering drugs. To preparethe pharmaceutical compositions of this invention, an effective amountof the particular compound, optionally in acid-addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which career may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules, and tablets. Because of their ease in administration, tabletsand capsules represents the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large pan, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Also includedare solid form preparations which are intended to be convened, shortlybefore use, to liquid form preparations. In the compositons suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not introduce a significant deleterious effect on theskin.

As appropriate compositions for topical application there may be citedall compositions usually employed for topically administering drugs,e.g., creams, gellies, dressings, shampoos, tinctures, pastes,ointments, salves, powders, liquid or semi-liquid formulation and thelike. Application of said compositions may be by aerosol e.g. with apropellent such as nitrogen carbon dioxide, a freon, or without apropellent such as a pump spray, drops, lotions, or a semisolid such asa thickened composition which can be applied by a swab. In particularcompositions, semisold compositions such as salves, creams, pastes,gellies, ointments and the like will conveniently be used.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discreate unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powders packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Other such compositions are preparations of the cosmetic type, such astoilet waters, packs, lotions, skin milks or milky lotions. Saidpreparations contain, besides the active ingredient of formula (I) or(II), components usually employed in such preparations. Examples of suchcomponents are oils, fats, waxes, surfactants, humechants, thickeningagents, antioxidants, viscosity stabilizers, chelating agents, buffers,preservatives, perfumes, dyestuffs, lower alkanols, and the like. Ifdesired, further ingredients may be incorporated in the compositions,e.g. antiinflammatory agents, antibacterials, antifungals,disinfectants, vitamins, sunscreens, antibiotics, or other anti-acneagents.

Examples of oils comprise fats and oils such as olive oil andhydrogenated oils; waxes such as beeswax and lanolin; hydrocarbons suchas liquid paraffin, ceresin, and squalane; fatty acids such as stearicacid and oleic acid; alcohols such as cetyl alcohol, stearyl alcohol,lanolin alcohol, and hexadecanol: and esters such as isopropylmyristate, isopropyl palmitate and butyl stearate. As examples ofsurfactants there may be cited anionic surfactants such as sodiumstearate, sodium cetylsulfate, polyoxyethylene laurylether phosphate,sodium N-acyl glutamate; cationic surfactants such asstearyldimethylbenzylammonium chloride and stearyltrimethylammoniumchloride; ampholytic surfactants such as alkylaminoethylglycinehydrochloride solutions and lecithin; and nonionic surfactants such asglycerin monostearate, sorbitan monostearate, sucrose fatty acid esters,propylene glycol monostearate, polyoxyethylene oleylether, polyethyleneglycol monostearate, polyoxyethylene sorbitan monopalmitate,polyoxyethylene coconut fatty acid monoethanolamide, polyoxyethylenepolyoxypropylene glycol (e.g. the materials sold under the trademark"Pluronic"), polyoxyethylene castor oil, and polyoxyethylene lanolin.Examples of humectants include glycerin, 1,3-butylene glycol, andpropylene glycol; examples of lower alcohols include ethanol andisopropanol; examples of thickening agents include xanthan gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethyleneglycol and sodium carboxymethyl cellulose; examples of antioxidantscomprise butylated hydroxytoluene, butylated hydroxyanisole, propylgallate, citric acid and ethoxyquin; examples of chelating agentsinclude disodium edetate and ethanehydroxy diphosphate; examples ofbuffers comprise citric acid, sodium citrate, boric acid, borax, anddisodium hydrogen phosphate; and examples of preservatives are methylparahydroxybenzoate, ethyl parahydroxybenzoate, dehydroacetic acid,salicylic acid and benzoic acid.

For preparing ointments, creams, toilet waters, skin milks, and thelike, typically from 0.01 to 10% in particular from 0.1 to 5% and morein particular from 0.2 to 2.5% of the active ingredient of formula (I)or (II) will be incorporated in said compositions. In ointments orcreams, the carrier for example consists of 1 to 20%, in particular 5 to15% of a humectant, 0.1 to 10% in particular from 0.5 to 5% of athickener and water; or said carrier may consist of 70 to 99%, inparticular 20 to 95% of a surfactant, and 0 to 20%, in particular 2.5 to15% of a fat; or 80 to 99.9% in particular 90 to 99% of a thickener: or5 to 15% of a surfactant, 2-15% of a humectant, 0 to 80% of an oil, verysmall (<2%) amounts of preservative, colouring agent and/or perfume, andwater. In a toilet water, the carrier for example consists of 2 to 10%of a lower alcohol, 0.1 to 10% or in particular 0.5 to 1% of asurfactant, 1 to 20%, in particular 3 to 7% of a humectant, 0 to 5% of abuffer, water and small amounts (<2%) of preservative, dyestuff and/orperfume. In a skin milk, the carrier typically consists of 10-50% ofoil, 1 to 10% of surfactant, 50-80% of water and 0 to 3% of preservativeand/or perfume. In the aforementioned preparations, all % symbols referto weight by weight percentage. The humectant, surfactant, oil, etc. . .. referred to in said preparations may be any such component used in thecosmetic arts but preferably will be one or more of the componentsmentioned hereinabove. Further, when in the above compositions one ormore of the components make up the major part of the composition, theother ingredients can evidently be not present at their indicatedmaximum concentration and therefore will make up the remainder of thecomposition.

Particular compositions for use in the method of the present inventionare those wherein the active ingredient of formula (I) or (II) isformulated in liposome-containing compositions. Liposomes are artificialvesicles formed by amphiphatic molecules such as polar lipids, forexample, phosphatidyl cholines, ethanolamines and serines,sphingomyelins, cardiolipins, plasmalogens, phosphatidic acids andcerebiosides. Liposomes are formed when suitable amphiphathic moleculesare allowed to swell in water or aqueous solutions to form liquidcrystals usually of multilayer structure comprised of many bilayersseparated from each other by aqueous material (also referred to ascoarse liposomes). Another type of liposome known to be consisting of asingle bilayer encapsulating aqueous material is referred to as aunilamellar vesicle. If water-soluble materials are included in theaqueous phase during the swelling of the lipids they become entrapped inthe aqueous layer between the lipid bilayers.

Water-soluble active ingredients such as, for example, most of the saltforms of the compound of formula (I) or (II) are encapsulated in theaqueous spaces between the molecular layers. The lipid soluble activeingredient of formula (I) or (II) is predominantly incorporated into thelipid layers, although polar head groups may protrude from the layerinto the aqueous space. The encapsulation of these compounds can beachieved by a number of methods. The method most commonly used involvescasting a thin film of phospholipid onto the walls of a flask byevaporation from an organic solvent. When this film is dispersed in asuitable aqueous medium, multilamellar liposomes are formed. Uponsuitable sonication, the coarse liposomes form smaller similarly closedvesicles.

Water-soluble active ingredients are usually incorporated by dispersingthe cast film with an aqueous solution of the compound. Theunencapsulated compound is then removed by centrifugation,chromatography, dialysis or other art-known suitable procedures. Thelipid-soluble active ingredient is usually incorporated by dissolving itin the organic solvent with the phospholipid prior to casting the film.If the solubility of the material in the lipid phase is not exceeded orthe amount present is not in excess of that which can be bound to thelipid, liposomes prepared by the above method usually contain most ofthe material bound in the lipid bilayers; separation of the liposomesfrom unencapsulated material is not required.

A particularly convenient method for preparing liposome formulated formsof the active ingredient of formula (I) or (II) is the method describedin EP-A-253,619, incorporated herein by reference. In this method,single bilayered liposomes containing encapsulated active ingredientsare prepared by dissolving the lipid component in an organic medium,injecting the organic solution of the lipid component under pressureinto an aqueous component while simultaneously mixing the organic andaqueous components with a high speed homogenizer or mixing means,whereupon the liposomes are formed spontaneously.

The single bilayered liposomes containing the encapsulated activeingredient of formula (I) or (II) can be employed directly or they canbe employed in a suitable pharmaceutically acceptable carrier fortopical administration. The viscosity of the liposomes can be increasedby the addition of one or more suitable thickening agents such as, forexample xanthan gum, hydroxypropyl cellulose, hydroxypropylmethylcellulose and mixtures thereof. The aqueous component may consistof water alone or it may contain electrolytes, buffered systems andother ingredients, such as, for example, preservatives. Suitableelectrolytes which can be employed include metal salts such as alkalimetal and alkaline earth metal salts. The preferred metal salts arecalcium chloride, sodium chloride and potassium chloride. Theconcentration of the electrolyte may vary from zero to 260 mM,preferably from 5 mM to 160 mM. The aqueous component is placed in asuitable vessel which can be adapted to effect homogenization byeffecting great turbulence during the injection of the organiccomponent. Homogenization of the two components can be accomplishedwithin the vessel, or, alternatively, the aqueous and organic componentsmay be injected separately into a mixing means which is located outsidethe vessel. In the latter case, the liposomes are formed in the mixingmeans and then transferred to another vessel for collection purpose.

The organic component consists of a suitable non-toxic, pharmaceuticallyacceptable solvent such as, for example ethanol, glycerol, propyleneglycol and polyethylene glycol, and a suitable phospholipid which issoluble in the solvent. Suitable phospholipids which can be employedinclude lecithin, phosphatidylcholine, phosphatidylethanol-amine,phosphatydylserine, phosphatidylinositol, lysophosphatidylcholine andphospha-tidyl glycerol, for example. Other lipophilic additives may beemployed in order to selectively modify the characteristics of theliposomes. Examples of such other additives include stearylamine,phosphatidic acid, tocopherol, cholesterol and lanolin extracts.

It may be advantageous to use micronized forms of the active ingredientof formula (I) or (II), i.e., material having an average particle sizeof less than 10 microns, as the high surface area will facilitate thedissolution of the liposomal components.

In addition, other ingredients which can prevent oxidation of thephospholipids may be added to the organic component. Examples of suchother ingredients include tocopherol, butylated hydroxyanisole,butylated hydroxytoluene, ascorbyl palmitate and ascorbyl oleate.Preservatives such as benzoic acid, methyl paraben and propyl parabenmay also be added.

The liposome-formulated forms of the active ingredient of formula (I) or(II), particularly those obtained in the above-referred method ofpreparing such liposome formulated forms, may be used as such or incombination with any of the aforementioned carriers to prepareointments, creams, gelees, toilet waters, etc. . . .

Apart from the above-described compositions, use may be made of covers,e.g. plasters, bandages, dressings, gauze pads and the like, containingan appropriate amount of a composition as referred hereinabove. In somecases use may be made of plasters, bandages, dressings, gauze pads andthe like which have been impregnated or sprinkled with a liquidformulation containing the active agent, e.g. with an aseptic aqueoussolution, or strewn with a powdery solid composition, or smeared,covered or coated with a semi-liquid composition.

In a further aspect of the invention there are provided particularpharmaceutical or cosmetical compositions which comprise an inertcarrier, an effective amount of a compound of formula (I) and/or (II),an acid addition salt or a stereochemically isomeric form thereof and aneffective amount of a retinoic acid, a derivative thereof or astereochemically isomeric form thereof.

It can be demonstrated that the retinoic acids and the compounds offormula (I) and/or (II) act in a synergistic manner. Indeed, thecombined effect of both substances is greater than the sum of theirrespective effects when administered separately. As evidenced by thedata obtained in the "vaginal keratinization"-test describedhereinafter. The above described retinoic acid containing compositionsare particularly useful for treating acne or for retarding the effectsof aging of the skin and generally improve the quality of the skin,particularly human facial skin. A pharmaceutical or cosmeticalcomposition containing retinoic acid or a derivative thereof as theactive ingredient in intimate admixture with a dermatologicallyacceptable carrier can be prepared according to conventional compoundingtechniques, such as those known for topical application of retinoic acidand its derivatives. Conventional pharmaceutical compounding techniquesfor topical application of retinoic acid are described for example in,U.S. Pat. Nos. 3,906,108 and 4,247,547, which are incorporated herein byreference. Preferred composition for topical application are in form ofa cream, ointment or lotion comprising from 0.005 to 0.5% (particularlyfrom 0.01 to 0.1%) all-trans-retinoic acid, 13-cis-retinoic acid or aderivative thereof and from 0.1 to 5% of a compound of formula (I)and/or (II), a dermatologically acceptable acid addition salt thereof ora stereochemically isomeric form thereof, in a semi-solid or liquiddiluent or carrier.

These preferred composition should preferably be non-irritating and asfar as possible they should be odorless and non-toxic. For conveniencein applying to the skin, the composition usually contain, besides wateror an organic solvent, several of certain organic emollients,emulsifiers for the aqueous and/or non aqueous phases of thecompositions, wetting agents preservatives and agents that facilitatethe penetration and remainence of the active agents in the skin.

In use, the retinoic acid containing compositions of the invention areapplied topically to the area to be treated or protected, at regularintervals, as needed, generally about 7 to about 21 times per week. Theduration of the treatment will depend upon the nature and severity ofthe condition to be treated as well as the frequency of application ofthe composition.

The following examples are intended to illustrate the scope of thepresent invention in all its aspects, and not to limit it thereto.

Experimental part

A. Preparation of the compounds

EXAMPLE 1

A mixture of 29.4 parts of5-[chloro(3-chlorophenyl)methyl]-2-methyl-1H-benzimidazolemonohydrochloride, 18.6 parts of 1H-1,2,3-triazole and 240 parts ofacetonitrile was stirred for 3 hours at reflux temperature. Afterevaporation to dry, the residue was taken up in water and treated withpotassium carbonate. The product was extracted three times with 39 partsof dichloromethane. The combined extracts were dried, filtered andevaporated to dry. The residue was purified by column chromatographyover silica gel using a mixture of dichloromethane and methanol (95:5 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was converted into the ethanedioate salt inethanol. The salt was filtered off and recrystallized from a mixture ofethanol and 2-propanone. The product was filtered off and dried,yielding 6.3 parts (14.0%) of5-[(3-chlorophenyl)(1H-1,2,3-triazol-1-yl)methyl]-2-methyl-1H-benzimidazoleethanedioate(1:2); mp. 205.4° C. (comp.31). EXAMPLE 2

A mixture of 5.6 parts of 1-methyl-α-phenyl-1H-benzimidazole-5-methanol,4.05 parts of 1,1'-carbonylbis[1H-imidazole] and 54 partstetrahydrofuran was stirred for 4 hours at reflux temperature. Thetetrahydrofuran layer was evaporated and water was added to the residue.The decanted oil was dissolved in dichloromethane. The organic layer wasdried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane,methanol and methanol, saturated with ammonia, (90:5:5 by volume) aseluent. The pure fractions were collected and the eluent was evaporated.The residue was further purified by column chromatography over silicagel using a mixture of trichloromethane and methanol (93:7 by volume) aseluent. The pure fractions were collected and the eluent was evaporated.The residue was washed with 2,2'-oxybispropane and dried, yielding 2.9parts (42.9%) of5-[(1H-imidazol-1-yl)phenylmethyl]-1-methyl-1H-benzimidazole; mp. 138.7°C. (comp. 21).

EXAMPLE 3

A mixture of 6.2 parts of4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine, 6.5 parts ofethyl ethanimidate hydrochloride and 80 parts of ethanol was stirred for3 hours at reflux temperature. After evaporation to dry, the residue wastaken up in water and sodium carbonate. The product was extracted threetimes with 120 parts of trichloromethane. The combined extracts weredried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (95:5 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was convened into thehydrochloride salt in a mixture of 2-propanone and ethanol. The salt wasfiltered off and crystallized from a mixture of ethanol and 2-propanone.The product was filtered off and dried, yielding 4 parts (44% ) of5-[1-(1H-imidazol-1yl)-2-methylpropyl]-2-methyl-1H-benzimidazoledihydrochloride.monohydrate; mp. 214.8° C. (comp. 22).

EXAMPLE 4

To a stirred and cooled (5° C.) solution of 5.2 parts of4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine in 4.8 parts ofacetic acid and 20 parts of water was added a solution of 1.38 parts ofsodium nitrite in 10 parts of water. The whole was stirred for 1 hour atroom temperature. The reaction mixture was treated with a sodiumhydrogen carbonate solution and the product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was crystallized from 64 parts of ethyl acetate. The product wasfiltered off and dried, yielding 4.7 parts (85.3%) of5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazole; mp. 178.8° C.(comp. 35).

All other compounds listed in Tables I and II can be obtained byanalogous methods of preparation.

B. Pharmaceutical Examples

EXAMPLE 5

Metabolism of exogenously administered all-trans-retinoic acid

Male Wistar rats weighing 200˜210 g were orally treated with vehicle(PEG 200) or with 40 mg/kg of a compound of formula (I). One hour later,the animals were anesthetized with ether and injected intrajugularlywith 0.50 ml saline solution containing 20 μg of all-trans-retinoicacid. Two hours after this injection, rats were killed by decapitationand blood was collected on heparin. Blood samples were centrifuged (1000g, 15 min) and plasma was recovered to determine the quantity ofplasmatic all-trans-retinoic acid. The samples were analyzed by means ofHPLC with UV-detection at 350 nm. Qualification was achieved by peakarea integration and external standardization. Under the conditionsused, plasma concentrations of the retinoic acid in vehicle-pretreatedanimals were not detectable (<0.5 ng/ml), whereas compound nos. 1, 2, 3,4, 5, 6, 7, 8, 9, 11, 13, 19, 20, 21, 22, 24, 28, 29, 30, 33 and 34enhanced the recovery of all-trans-retinoic acid from the plasma to aleast 8 ng/ml after dosing with 40 mg/kg.

EXAMPLE 6

Metabolism of endogenous all-trans-retinoic acid

Male Wistar rats weighing 200˜210 g were orally treated with vehicle(PEG 200) or with 40 mg/kg of a compound of formula (I). Two hours afterdrug administration, the rats were killed by decapitation and blood wascollected on heparin. Blood samples were centrifuged (1000 g, 15 min)and plasma was recovered to determine the quantity of plasmaticall-trans-retinoic acid. The samples were analyzed by means of HPLC withUV-detection at 350 nm. Qualification was achieved by peak areaintegration and external standardization. Under the conditions used,plasma concentrations of the retinoic acid in vehicle-pretreated animalswere not detectable (<0.5 ng/ml), whereas compound nos. 1, 2, 7, 13, 21,22, 27, 28 and 33 enhanced the,recovery of all-trans-retinoic acid fromthe plasma to a least 1 ng/ml.

EXAMPLE 7

Vaginal keratinization.

Ovariectomized rats were injected subcutaneously with a sesame oilsolution containing 100 μg of estradiol undecylate (Progynon Depot®,Schering) in a volume of 0.1 ml per 100 g body weight. One and two dayslater, the animals were treated intravaginally with 200 μl of vehicle(PEG 200), all-trans-retinoic acid (1 or 4 μg) or all-trans-retinoicacid (1 μg) together with 3 mg of a compound of formula (I). One dayafter the second topical treatment, the animals were sacrificed. Vaginaswere immediately dissected and trimmed of fat and connective tissue. Thethird middle of the organ (0.5 cm length) was fixed in liquid nitrogenfor histological analysis. Hereto, a series of 10 μm cross-section werecut at -25° C., mounted onto gelatin-coated glass slides and stainedwith hematoxylin and eosin. The slides were examined under lightmicroscopy at 100-400×magnification. The condition of the vaginal mucosawas scored (keratinization score) as

0: absence of keratinized squamae attached to the epithelial cells.

+: presence of keratinized squamae partially covering the epithelialcells.

++: presence of keratinized squamae covering the entire vaginalepithellium.

Results

    ______________________________________                                                              score                                                   ______________________________________                                        vehicle (PEG 200)       ++                                                    4 μg retinoic acid   0                                                     1 μg retinoic acid   ++                                                    1 μg retinoic acid + 3 mg comp. No. 21                                                             0                                                     ______________________________________                                    

C) Composition Examples

The following formulations exemplify typical pharmaceutical andcosmetical compositions in dosage unit form suitable for systemic ortopical administration to warm-blooded animals in accordance with thepresent invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof.

EXAMPLE 8: ORAL DROPS

500 g of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acid and1.5 l of the polyethylene glycol at 60°≈80° C. After cooling to 30°40°C. there were added 35 l of polyethylene glycol and the mixture wasstirred well. Then there was added a solution of g of sodium saccharinin 2.5 l of purified water and while stirring there were added 2.5 l ofcocoa flavor and polyethylene glycol q.s. to a volume of 50 l, providingan oral drop solution comprising 10 mg of the A.I. (per ml). Theresulting solution was filled into suitable containers.

EXAMPLE 9: ORAL SOLUTION

9 g of methyl 4-hydroxybenzoate and 1 part of propyl 4-hydroxy-benzoatewere dissolved in 4 l of boiling purified water. In 3 l of this solutionwere dissolved first 10 g of 2,3-dihydroxybutanedioic acid andthereafter 20 g of the A.I. The latter solution was combined with theremaining pan of the former solution and 12 l 1,2,3-propane-triol and 3l of sorbitol 70% solution were added thereto. 40 g of sodium saccharinwere dissolved in 0.5 l of water and 2 ml of raspberry and 2 ml ofgooseberry essence were added. The latter solution was combined with theformer, water was added q.s. to a volume of 20 l providing an oralsolution comprising 5 mg of the A.I. per teaspoonful (5 ml). Theresulting solution was filled in suitable containers.

EXAMPLE 10: CAPSULES

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose,0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate werevigorously stirred together. The resulting mixture was subsequentlyfilled into 1000 suitable hardened gelatin capsules, each comprising 20mg of the A.I.

EXAMPLE 11: FILM-COATED TABLETS

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90®) in about 200 mlof water. The wet powder mixture was sieved, dried and sieved again.Then there was added 100 g microcrystalline cellulose (Avicel®) and 15 ghydrogenated vegetable oil (Sterotex®). The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each comprising 10 mg ofthe active ingredient.

Coating

To a solution of 10 g methyl cellulose (Methocel 60 HG®) in-75 ml ofdenaturated ethanol there was added a solution of 5 g of ethyl cellulose(Ethocel 22 cps®) in 150 ml of dichloromethane. Then there were added 75ml of dichloromethane and 2.5 ml 1,2,3-propane-triol. 10 g ofpolyethylene glycol was molten and dissolved in 75 ml ofdichloromethane. The latter solution was added to the former and thenthere were added 2.5 g of magnesium octadecanoate, 5 g ofpolyvinylpyrrolidone and 30 ml of concentrated colour suspension(Opaspray K-1-2109®) and the whole was homogenated. The tablet coreswere coated with the thus obtained mixture in a coating apparatus.

EXAMPLE 12: INJECTABLE SOLUTION

1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate weredissolved in about 0.5 l of boiling water for injection. After coolingto about 50° C. there were added while stirring 4 g lactic acid, 0.05 gpropylene glycol and 4 g of the A.I. The solution was cooled to roomtemperature and supplemented with water for injection q.s. ad 1 lvolume, giving a solution of 4 mg A.I. per ml. The solution wassterilized by filtration (U.S.P. XVII p. 811) and filled in sterilecontainers.

EXAMPLE 13: SUPPOSITORIES

3 g A.I. was dissolved in a solution of 3 g 2,3-dihydroxybutane-dioicacid in 25 ml polyethylene glycol 400. 12 g surfactant (SPAN(®) andtriglycerides (Witepsol 555®) q.s. ad 300 g were molten together. Thelatter mixture was mixed well with the former solution. The thusobtained mixture was poured into moulds at a temperature of 37°-38° C.to form 100 suppositories each containing 30 mg of the activeingredient.

EXAMPLE 14: 2% CREAM

75 mg of stearyl alcohol, 2 mg of cetyl alcohol, 20 mg of sorbitanmonostearate and 10 mg of isopropyl myristate are introduced into adoublewall jacketed vessel and heated until the mixture has completelymolten. This mixture is added to a separately prepared mixture ofpurified water, 200 mg of propylene glycol and 15 mg of polysorbate 60having a temperature of 70° to 75° C. while using a homogenizer forliquids. The resulting emulsion is allowed to cool to below 25° C. whilecontinuously mixing. A solution of 20 mg of active ingredient of formula(I) or (II), 1 mg of polysorbate 80 and purified water and a solution of2 mg of sodium sulfite anhydrous in purified water are next added to theemulsion while continuously mixing. The cream (1 g) is homogenized andfilled into suitable tubes.

EXAMPLE 15: 2% TOPICAL GEL

To a solution of 200 mg of hydroxypropyl β-cyclodextrine in purifiedwater is added 20 mg of active ingredient of formula (I) or (II) whilestirring. Hydrochloric acid is added until complete solution and thensodium hydroxide is added until pH 6.0. This solution is added to adispersion of 10 mg of carrageenan PJ in 50 mg of propylene glycol whilemixing. While mixing slowly the mixture is heated to 50° C. and allowedto cool to about 35° C. whereupon 50 mg of ethyl alcohol 95% is added.The rest of the purified water is added q.s. ad 1 g and the mixture ismixed to homogenous.

EXAMPLE 16: 2% TOPICAL CREAM

To a solution of 200 mg of hydroxypropyl β-cyclodextrine in purifiedwater is added 20 mg of active ingredient of formula (I) or (II) whilestirring. Hydrochloric acid is added until complete solution and nextsodium hydroxide is added until pH 6.0. While stirring, 50 mg ofglycerol and 35 mg of polysorbate 60 are added and the mixture is heatedto 70° C. The resulting mixture is added to a mixture of 100 mg ofmineral oil, 20 mg of stearyl alcohol, 20 mg of cetyl alcohol, 20 mg ofglycerol monostearate and 15 mg of sorbate 60 having a temperature of70° C. while mixing slowly. After cooling down to below 25° C., the restof the purified water is added q.s. ad 1 g and the mixture is mixed tohomogenous.

EXAMPLE 17: 2% LIPOSOME FORMULATION

A mixture of 2 g of active ingredient of formula (I) or (II) microfine,20 g of phosphatidyl choline, 5 g of cholesterol and 10 g of ethylalcohol is stirred and heated at 55°-60° C. until complete solution andis added to a solution of 0.2 g of methyl paraben, 0.02 g of propylparaben, 0.15 g of disodium edetate and 0.3 g of sodium chloride inpurified water while homogenizing. 1.5 g of hydroxypropylmethylcellulosein purified water is added ad 100 g and the mixing is continued untilswelling is complete.

EXAMPLE 18: 2% LlPOSOME FORMULATION

A mixture of 10 g of phosphatidyl choline and 1 g of cholesterol in 7.5g of ethyl alcohol is stirred and heated at 40° C. until completesolution. 2 g of active ingredient of formula (I) or (II) microfine isdissolved in purified water by mixing while heating at 40° C. Thealcoholic solution is added slowly to the aqueous solution whilehomogenizing during 10 minutes. 1.5 g of hydroxypropylmethylcellulose inpurified water is added while mixing until swelling is complete. Theresulting solution is adjusted to pH 5.0 with sodium hydroxide 1N anddiluted with the rest of the purified water ad 100 g.

We claim:
 1. A pharmaceutical or cosmetic composition comprising aninert carrier, an effective amount of a retinoic acid, a derivativethereof or a stereochemically isomeric form thereof and an effectiveamount of a compound of formula ##STR25## a pharmaceutically acceptableacid addition salt thereof or a stereochemically isomeric form thereof,whereinR, R¹, R², --A¹ ═A² --A³ ═A⁴ -- and A in formula (I) have thefollowing meaning --A¹ ═A² --A³ ═A⁴ -- is a bivalent radical having theformula

    --CH═N--CH═CH--                                    (x);

    --CH═N--CH═N--                                     (y); or

    13 CH═N--N═CH--                                    (z);

R is hydrogen or C₁₋₆ alkyl; R¹ is hydrogen; C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; Ar¹ or Ar¹ --C₁₋₆ alkyl; R² is hydrogen; C₃₋₇ cycloalkyl;Ar¹ ; C₁₋₁₀ alkyl; C₁₋₆ alkyl substituted with Ar¹ or C₃₋₇ cycloalkyl;hydroxy; C₁₋₁₀ alkyloxy; C₁₋₆ alkyloxy substituted with Ar¹ or C₃₋₇cycloalkyl; C₃₋₆ alkenyloxy optionally substituted with Ar² ; C₃₋₆alkynyloxy optionally substituted with Ar² ; or Ar¹ -oxy; A is abivalent radical having the formula ##STR26## wherein the carbon atom inthe bivalent radical (a) and (b) is connected to --NR² ; said R³ beinghydrogen; halo; C₁₋₄ alkyl substituted with up to 4 halo atoms; C₃₋₇cycloalkyl; Ar¹ ; quinolinyl; indolinyl; C₁₋₁₀ alkyl; C₁₋₆ alkylsubstituted with Ar¹, C₃₋₇ cycloalkyl, quinolinyl, indolinyl or hydroxy;C₁₋₁₀ alkyloxy; C₁₋₆ alkyloxy substituted with Ar¹ or C₃₋₇ cycloalkyl;C₂₋₆ alkenyl optionally substituted with Ar¹ ; Ar² -oxy; C₁₋₆alkyloxycarbonyl; carboxyl; C₁₋₆ alkylcarbonyl; Ar¹ -carbonyl or Ar¹--(CHOH)--; said X being O or S; said R⁴ being hydrogen, C₁₋₆ alkyl orAr² --C₁₋₆ alkyl; wherein Ar¹ is phenyl, substituted phenyl, pyridinyl,aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranylor thiazolyl; and Ar² is phenyl or substituted phenyl; said substitutedphenyl in Ar¹ and Ar² being phenyl substituted with 1, 2 or 3substituents each independently selected from halo, hydroxy,trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, cyano, amino, mono- anddi(C₁₋₆ alkyl)amino, nitro, carboxyl, formyl and C₁₋₆ alkyloxycarbonyl;and wherein R, R⁵, R⁶, R⁷ and --A¹ ═A² --A³ ═A⁴ -- in formula (II) havethe following meaning --A¹ ═A² --A³ ═A⁴ -- is a bivalent radical havingthe formula

    --CH═N--CH═CH--                                    (x);

    --CH═N--CH═N--                                     (y); or

    --CH═N--N═CH--                                     (z);

R is hydrogen or C₁₋₆ alkyl; R⁵ is hydrogen; C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; Ar³ ; Ar⁴ --C₁₋₆ alkyl; C₂₋₆ alkenyl or C₂₋₆ alkynyl; R⁶ ishydrogen; C₁₋₁₀ alkyl optionally substituted with Ar³, C₃₋₇ cycloalkyl,hydroxy or C₁₋₆ alkyloxy; Ar³ ; C₂₋₆ alkenyl; C₂₋₆ alkynyl; C₃₋₇cycloalkyl; bicyclo[2.2.1]heptan-2-yl; 2,3-dihydro-1H-indenyl;1,2,3,4-tetrahydronaphthalenyl; or a radical of formula OR⁷, R⁷ ishydrogen; C₂₋₆ alkenyl optionally substituted with Ar⁴ ; C₂₋₆ alkynyl;pyrimidinyl, di(Ar⁴)methyl; 1-C₁₋₄ alkyl-4-piperidinyl; or C₁₋₁₀ alkyloptionally substituted with halo, hydroxy, C₁₋₆ alkyloxy, amino, mono-and di(C₁₋₆ alkyl)-amino, trifluoromethyl, carboxyl, C₁₋₆alkyloxycarbonyl, Ar³, Ar⁴ --O--, Ar⁴ --S--, C₃₋₇ cycloalkyl,2,3-dihydro-1,4-benzodioxinyl, 1H-benzimidazolyl, C₁₋₄ alkyl substituted1H-benzimidazolyl, (1,1'-biphenyl)-4-yl or with2,3-dihydro-2-oxo-1H-benzimidazolyl; R⁸ is hydrogen, nitro, amino, mono-and di(C₁₋₆ alkyl)amino, halo, C₁₋₆ alkyl, hydroxy or C₁₋₆ alkyloxy;wherein Ar³ is phenyl, substituted phenyl, naphthalenyl, pyridinyl,aminopyridinyl, imidazolyl, triazolyl, thienyl, halothienyl, furanyl,C₁₋₆ alkylfuranyl, halofuranyl or thiazolyl; Ar⁴ is phenyl, substitutedphenyl or pyridinyl, said substituted phenyl in Ar³ and Ar⁴ being phenylsubstituted with up to 3 substituents each independently selected fromhalo, hydroxy, hydroxymethyl, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆alkyloxy, C₁₋₆ alkyloxycarbonyl, carboxyl, formyl, (hydroxyimino)methyl,cyano, amino, mono- and di(C₁₋₆ alkyl)amino and nitro.
 2. A compositionaccording to claim 1 wherein said retinoic acid is all-trans-retinoicacid.
 3. A composition according to claim 1 wherein retinoic acid is13-cis-retinoic acid.
 4. The composition of claim 1 wherein the compoundof Formula (I) is 5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzimidazole, a pharmaceuticallyacceptable acid addition salt thereof, or a stereochemically isomericform thereof.
 5. A method of treating subjects suffering from disorderswhich are characterized by an increased proliferation and/or abnormaldifferentiation of normal, preneoplastic or neoplastic epithelial cellsby the systemic or topical administration to said subjects of acomposition as defined in claim
 1. 6. A method of treating subjectssuffering from disorders which are characterized by an increasedproliferation and/or abnormal differentiation of normal, preneoplasticor neoplastic epithelial cells by the systemic or topical administrationto said subjects of a composition as defined in claim
 1. 7. A method oftreating subjects suffering from disorders which are characterized by anincreased proliferation and/or abnormal differentiation of normal,preneoplastic or neoplastic epithelial cells by the systemic or topicaladministration to said subjects of a composition as defined in claim 3.8. A method of treating subjects suffering from disorders which arecharacterized by an increased proliferation and/or abnormaldifferentiation of normal, preneoplastic or neoplastic epithelial cellsby the systemic or topical administration to said subjects of acomposition as defined in claim 4.